ES2900283T3 - Improved process for the manufacture of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3 hydrochloride (4H)-one - Google Patents

Abstract

A camphorsulfonate salt of intermediate (4), where PG is C1-C10 alkyl substituted by a C6-C10 aryl group **(See formula)**

Description

DESCRIPTION

Improved process for the manufacture of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3 hydrochloride (4H)-one

field of invention

The present invention provides an improved process for the manufacture of olodaterol or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt, with high chemical and enantiomeric purity and high yield, through the camphorsulfonate salt of intermediate (4). The invention also relates to said salts, a process for preparing them and their uses for the manufacture of olodaterol or a pharmaceutically acceptable salt thereof.

Background of the invention

(R)-6-Hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3(4H)-one, the compound of formula (1), also known as the R-enantiomer of olodaterol, is a long-acting p ² -adrenergic receptor agonist (LABA), marketed as its hydrochloride salt under the trade name Striverdi® Respimat®, for the once-daily treatment of chronic obstructive pulmonary disease (COPD).

The document no. WO 2004/045618 A2 first describes the preparation of racemic olodaterol by reacting an intermediate glyoxal hydrate with 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine in the presence of a hydride source. After hydrogenation, the racemic olodaterol is recrystallized and the R-enantiomer is separated by chiral chromatography. This process is not feasible for industrial application since the preparation of the objective R -enantiomer of olodaterol is carried out by means of chiral chromatographic methods, which are generally expensive, harmful to the environment and time consuming. Furthermore, the preparation and purity of the intermediate 1,1-dimethyl-2(4-methoxyphenyl)ethyl amine is not disclosed.

The document no. WO 2005/111005 A1 describes the preparation of the R-enantiomer of olodaterol hydrochloride, compound of formula (1) HCl, as shown in Scheme 1. Basically, (R)-6-benzyloxy-8-oxiranil -4H-benzo[1,4]oxazin-3-one (2) with 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine in isopropanol under microwave irradiation at 135 °C to give advanced intermediate (4 ), which is purified by column chromatography and further recrystallized. The R-enantiomer of olodaterol hydrochloride is obtained after hydrogenation and subsequent reaction with hydrochloric acid. Advanced intermediate (4) is obtained in only 63% yield and purity is not disclosed. This process involves several drawbacks. Not only the microwave radiation technique is not easily feasible for industrial application, but also the purification of the advanced intermediate (4) by chromatographic methods. Furthermore, the preparation and purity of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine is not disclosed.

Scheme 1

The document no. WO 2007/020227 A1 describes the preparation of the R-enantiomer of olodaterol hydrochloride as shown in Scheme 2. In particular, (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4] oxazin-3-one (2) with 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine (3) in 1,4-dioxane at 97 °C, then treated with hydrochloric acid to give the salt hydrochloride of advanced intermediate (4), which is further hydrogenated. Intermediate E1HCl (4) is obtained in 89.5-99.5% purity.

The document no. WO 2007/020227 A1 also describes the preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine (3) from 4-methoxyphenylacetone (5), in three reaction steps as shown in Scheme 3 , in 94-96% purity (HPLC method) with an overall yield of 34-43% (calculated from the data of the examples given in WO 2007/020227 A1).

The document no. WO 2008/090193 A2 describes the preparation of the R-enantiomer of olodaterol hydrochloride as shown in Scheme 4. (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3 -one (2) with 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine (3) in refluxing toluene. Then treatment with hydrochloric acid to give intermediate (4) HCl in 95-99.5% purity, followed by a hydrogenation step gives the R-enantiomer of olodaterol hydrochloride. Furthermore, document no. Wo 2008/090193 A2 describes the preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride salt from 4-methoxyphenylacetone, as in Scheme 3 above, in >99.5% of purity (HPLC method) with an overall yield of 41-54% (calculated from the data of the examples given in WO 2008/090193 A2).

Scheme 4

The documents nos. WO 2007/020227 A1 and WO 2008/090193 A2 of the prior art describe the preparation of a 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine intermediate, either as a base or as its hydrochloride salt, with low yields, which implies the increase in the cost of the final process of olodaterol and pharmaceutical compositions containing it, which already resulted in expensive drugs.

The known process for preparing amines as key intermediates in the synthesis of new psychomimetic compounds (olodaterol not disclosed) is described in the article Archiv der Pharmazie (Weinheim, Germany), 1983, 316(3), pages 193-2011. Particularly, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride is prepared, as shown in Scheme 5, in 66% overall yield from 4-(2-methyl-2- nitropropyl)phenol in three synthesis steps. 4-(2-Methyl-2-nitropropyl)phenol, a compound of formula (6), is methylated to give intermediate nitro (7), which is further recrystallized. The nitro group is then reduced by hydrogenation and the obtained amine is treated with hydrochloric acid to give 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride. The purity is not described.

Scheme 5

Therefore, there is a need to develop feasible methods for the manufacture of olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, in high purity and high yield.

Brief description of the invention

The inventors have unexpectedly discovered that purifying intermediate (4), used in the process of preparing olodaterol, by forming the camphorsulfonate salt, in particular the (R)-(-)-camphorsulfonate salt, provides an increase in the chemical and enantiomeric purity of the final olodaterol or salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Thus, a first aspect of the present invention provides the camphorsulfonate salt of intermediate (4), wherein PG is C ¹ -C ¹⁰ alkyl substituted by a C ⁶ -C ¹⁰ aryl group, and solid forms thereof.

A second aspect of the present invention provides a process for preparing the camphorsulfonate salt of intermediate (4) as defined in the first aspect.

A third aspect of the present invention relates to a process for the manufacture of olodaterol, preferably the R-enantiomer of olodaterol hydrochloride, which makes use of the camphorsulfonate salt of intermediate (4) as defined in the first aspect.

Other aspects of the present invention relate to the use of the camphorsulfonate salt of intermediate (4) as defined in the first and second aspects to prepare olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Brief description of the drawings

The examples of the invention are illustrated with the following drawings:

Figure 1 shows the DSC analysis of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (not included in the invention) prepared as in example 2.

Figure 2 shows the TG analysis of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (not included in the invention) prepared as in example 2.

Figure 3 shows the IR analysis of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (not included in the invention) prepared as in example 2.

Figure 4 shows the IR analysis of the (R)-(-)-camphorsulfonate salt of intermediate (4), where PG is benzyl, prepared as in example 6.

Definitions

When describing the compounds and methods of the invention, the following terms have the following meanings, unless otherwise indicated.

The term "olodaterol" refers to 6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]- 2H-1,4-benzoxazin-3(4H)- one.

As used herein, the term "organic solvent" refers to an organic molecule capable of dissolving another substance (ie, the solute). Organic solvents can be liquid at room temperature. Examples of organic solvents that can be used for the present invention include, but are not limited to: hydrocarbon solvents (for example, n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, decahydronaphthalene, etc. .) which also includes aromatic hydrocarbon solvents (for example, benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (for example, carbon tetrachloride, 1,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (for example, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (for example, acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), ether solvents (for example, diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran , 2-methyltetrahydrofuran, 1,4-dioxane, methyl phenyl ether or anisole, etc.), amine solvents (for example, propylamine, diethylamine, triethylamine, aniline, pyridine), alcoholic solvents (for example, methanol, ethanol, isopropanol, 1-propanol , 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m- cresol, etc.), acid solvents (e.g. acetic acid, hexanoic acid, etc.), nitrobenzene, N,N-dimethylformamide, N,N,-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetonitrile, propionitrile , butyronitrile, silicone solvents (eg silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent can be formed by combining two or more organic solvents.

The term polar solvent, as used in the present description, means a solvent that has a dielectric constant of at least 3, said dielectric constant being the ratio between the electrical capacity of a capacitor filled with the solvent and the electrical capacity of the evacuated capacitor. at 20-25°C. Dielectric constant values for solvents are described in Vogel's Textbook of Practical Organic Chemistry 5th Edition, Appendix 5. Examples of polar solvents are dichloromethane, tetrahydrofuran, ester solvents (for example, ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (for example, acetone, methyl ethyl ketone or 2-butanone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), amine solvents (for example, propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (for example, methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc. .), acid solvents (for example, acetic acid, hexanoic acid, etc.), nitrobenzene, N,N-dimethylformamide, N,N,-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile propionitrile, butyronitrile and solvents silicone (e.g. oil) is silicone, polysiloxanes, cyclosilicones).

The term alcohol refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group, known as a hydroxyl group. Alcohols suitable for the present invention include C ¹ -C ⁶ linear, cyclic or branched alkyl alcohols and any mixtures thereof. It also includes commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol and phenol.

The term room temperature in the context of the present invention means that the temperature is between 10°C and 40°C, preferably between 15°C and 30°C, more preferably between 20°C and 25°C.

The term conventional purification techniques as used herein refers to the process where a product with high purity can be obtained, which can be carried out on an industrial scale, such as solvent extraction, filtration, distillation, washing or dispersion with solvent, washing, phase separation, evaporation, centrifugation, isolation or crystallization.

As used herein, the term solvent extraction refers to the process of separating components of a mixture by using a solvent that possesses a higher affinity for one component, and therefore can separate said component from at least one second component. which is less miscible than said component with said solvent.

The term filtration refers to the act of removing solid particles larger than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression filtrate refers to the mixture minus the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The term "filter cake" refers to residual solid material remaining on the feed side of a filter element.

As used herein, the term solvent washing or dispersing refers to any process that employs a solvent to wash or disperse a crude product.

As used herein, the term "washing" refers to the process of purifying a solid mass (eg, crystals) by passing a liquid over and/or through the solid mass in order to remove soluble matter. The process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtration, decantation, or combinations thereof. For example, in one embodiment of the invention, washing includes contacting the solids with solvent or mixture of solvents, shaking vigorously (eg, for two hours), and filtering. The solvent may be water, it may be an aqueous solvent system, or it may be an organic solvent system. Additionally, the washing can be carried out with the solvent at any suitable temperature. For example, the washing can be carried out with the solvent at a temperature between about 0°C and about 100°C.

The term phase separation refers to a solution or mixture that has at least two physically distinct regions.

The term crystallization refers to any method known to a person skilled in the art, such as crystallization from a single solvent or a combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing the solution solvent or both. That also includes methods such as solvent/antisolvent or precipitation.

The term polymorphic form or polymorph refers to crystalline forms of the same pure compound in which the molecules have different arrangements and/or different conformations of the molecules. As a result, polymorphic solids have different unit cells and thus display different physical properties, including those of packing, and various thermodynamic, spectroscopic, interfacial, and mechanical properties. The term solvate refers to solid molecular compounds that have incorporated the crystallizing solvent molecule into their network. When the solvent incorporated in the solvate is water, the solvate is called a hydrate. All solvates are formed with stoichiometric or non-stoichiometric ratios between the compound and the solvent of crystallization. Solvates may exhibit polymorphism, that is, they may exist in more than one polymorphic form. The term solid form includes all solid materials, polymorphs, solvates (including hydrates), amorphous solids, salts and co-crystals.

The term purification and/or purifying as used herein refers to the process whereby a purified pharmaceutical substance can be obtained, measured by HPLC, preferably having a purity greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%, more preferably greater than 99.5%, even more preferably greater than 99.9%. The term "industrial purification" refers to purifications, which can be carried out on an industrial scale, such as solvent extraction, filtration, solvent washing or dispersion, washing, phase separation, evaporation, centrifugation or crystallization.

The term olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, high chemical purity refers to a purity obtained by HPLC of at least 99%, preferably at least 99.5%, most preferably at least 99.9%, even more preferably at least 99.95% , even with the maximum preference of 100%.

The term olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, in high enantiomeric purity refers to an enantiomeric purity of the R-enantiomer measured by chiral HPLC of at least 99.85%, more preferably at least 99.90%. %, even more preferably at least 99.95%, even more preferably 100.00%.

The term "pharmaceutically acceptable salt" when characterizing salts of olodaterol refers to a salt prepared from a base or its respective conjugate acids, which is acceptable for administration to a patient, such as a mammal. Such salts may be derived from pharmaceutically acceptable organic or inorganic acids, including, but not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, camphorsulfonic, 1,5-naphthalene disulfonic, formic, acetic, benzoic, malonic, malic, citric, fumaric, gluconic, glycolic, glutamic, lactic, maleic, L-tartaric, oxalic, mandelic, mucic, pantothenic, succinic, xinaphoic (1-hydroxy-2-naphthoic acid) and cinnamic acid. Preferably, the pharmaceutically acceptable acid is hydrochloric acid.

The term (R)-camphorsulfonic acid refers to (R)-(-)-camphorsulfonic acid or (1R)-(-)-10-camphorsulfonic acid.

The term (S)-camphorsulfonic acid refers to (Sj-(+)-camphorsulfonic acid or (1S)-(+)-10-camphorsulfonic acid.

Detailed description of the invention

Camphorsulfonate salt of intermediate (4)

The inventors have realized that the epoxide opening reaction of the compound of formula (2) with amine (3) described in the documents nos. dWO2005/111005 A1, WO 2007/020227 A1 and WO 2008/090193 A ² in the prior art leads to the convenient advanced intermediate (4) in free base or hydrochloride salt form (previously shown in schemes 1, 2 and 4) , but always with the presence of a significant amount of impurities, which are difficult to remove from the final olodaterol. These impurities are compounds of the formula IMP-1, IMP-2, IMP-3 and IMP-4 which are depicted below.

The most significant is the dimeric impurity (IMP-1), which is the consequence of a second addition of the product initially obtained with another epoxide (2), as well as the formation of another isomer (IMP-2) that is the result of the addition of the amine (3) to the secondary carbon of the epoxide (2). The inventors have unexpectedly discovered that the purification of intermediate (4), obtained from the epoxide opening reaction, by the formation of the camphorsulfonate salt, significantly reduces the content of these impurities in a reproducible manner, and thus provides olodaterol end or salt thereof, preferably the R-enantiomer of Olodaterol hydrochloride, with high chemical and enantiomeric purity and high yield.

Thus, a first aspect of the present invention provides the camphorsulfonate salt of intermediate (4), the compound of formula ( ⁴ ) camphorsulfonic acid, and solid forms thereof, wherein PG is C1- ^C10 alkyl substituted by a group C ⁶ -C ¹⁰ aryl, more preferably benzyl or p-methoxybenzyl, still more preferably benzyl. The camphorsulfonate salt of intermediate (4) is obtained in high chemical and enantiomeric purity and high yield, and has good stability.

The camphorsulfonic acid that forms the salt of the invention can be (R)-camphorsulfonic acid, (S)-camphorsulfonic acid or mixtures thereof. In a preferred embodiment, the salt is the (R)-camphorsulfonate salt of intermediate (4). In another embodiment, the salt is the (S)-camphorsulfonate salt of intermediate (4). In a preferred embodiment, the salt is the (R)-camphorsulfonate salt of intermediate (4), where PG is benzyl, the structure of which is shown below.

In one embodiment, the molar ratio of intermediate (4) to camphorsulfonic acid is 1:1.

In a particular embodiment, the camphorsulfonate salt of intermediate (4) is in solid form. Preferably, the camphorsulfonate salt of intermediate (4) is in solid crystalline form. In an alternative embodiment, the camphorsulfonate salt of intermediate (4) is in a non-crystalline (ie amorphous) solid form. More preferably, the camphorsulfonate salt of intermediate (4) is the (R)-camphorsulfonate salt, where PG is benzyl, in crystalline solid form. More preferably, the (R)-camphorsulfonate salt of intermediate (4), where PG is benzyl, is an anhydrous solid form. In yet another embodiment, the (R)-camphorsulfonate salt of intermediate (4), where PG is benzyl, encompasses solvates (including hydrates).

In one embodiment, a solid crystalline form of the camphorsulfonate salt of intermediate (4), where PG is benzyl, is characterized by at least one of the following:

a) a DSC thermogram showing an endothermic peak with an onset at 163-166 °C, or

b) an IR spectrum showing the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm'1.

In a further embodiment, the (R)-camphorsulfonate salt of intermediate (4), where PG is benzyl, is characterized by a DSC thermogram showing an endothermic peak with an onset at 163-166°C.

Another embodiment, the (R)-camphorsulfonate salt of intermediate (4), where PG is benzyl, is characterized by an IR spectrum showing the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm'1.

In a further embodiment, the (R)-camphorsulfonate salt of intermediate (4), wherein PG is benzyl, is characterized in that it provides an IR spectrum substantially in accordance with Figure 4.

In an alternative embodiment, the salt is the (S)-camphorsulfonate of intermediate (4), where PG is benzyl.

A second aspect of the present invention provides a process for preparing the camphorsulfonate salt of intermediate (4) as defined in the first aspect, comprising the steps of:

a) treating the intermediate of formula (4), wherein PG is a hydroxyl protecting group as previously defined, with camphorsulfonic acid in the presence of a solvent or a mixture of solvents,

preferably PG is C1- ^C10 alkyl substituted by ^a C6- ^{C10 aryl} group, more preferably benzyl or p-methoxybenzyl and

a) isolating the camphorsulfonate salt obtained in step a).

The molar ratio of camphorsulfonic acid to intermediate (4) used in step a) of the aforementioned process is preferably at least 1:1, preferably 1:1 to 2:1, even more preferably 1:1 to 1 ,1:1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent comprises an organic solvent, water, or mixtures thereof. The suitable organic solvent is a polar solvent. Preferably, the solvent comprises a mixture of two polar solvents. Suitable polar solvents are ether and ester solvents. Suitable ethers are diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butylmethyl ether, tetrahydrofuran, and 1,4-dioxane, and mixtures thereof. Suitable esters are ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, and mixtures thereof. More preferably, the polar solvent comprises a mixture of an ether and an ester. More preferably, the organic solvent is a mixture of ester (in particular ethyl acetate) and tetrahydrofuran, preferably in a ratio of 15:1 to 1:15 (v/v). More preferably, the solvent comprises a mixture of an ester (particularly ethyl acetate) and tetrahydrofuran in a ratio of 15:1 to 1:1 (v/v). Also more preferably, an ester (in particular ethyl acetate) and tetrahydrofuran in a ratio of 15:1 to 10:1 (v/v) as the yield increases.

Step b), the isolation of the salt obtained in step a), can be carried out by conventional means, such as filtration followed optionally by washing. Preferably, the washing is carried out with a mixture of ester (in particular ethyl acetate) and tetrahydrofuran, preferably in a ratio of 6:1 to 4:1 (v/v).

In a particular embodiment, the camphorsulfonate salt can be purified by conventional purification techniques. In a preferred embodiment, the camphorsulfonate salt can be purified by crystallization. In an even more preferred embodiment, the (R)-camphorsulfonate salt of intermediate (4), preferably wherein PG is benzyl, is purified by crystallization. In another preferred embodiment, the (S)-camphorsulfonate salt of intermediate (4), preferably wherein PG is benzyl, is purified by crystallization.

A third aspect of the present invention provides a process for manufacturing olodaterol or a pharmaceutical salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, comprising the steps of:

a) providing the camphorsulfonate salt of compound (4) according to the first aspect of the invention b) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid, to provide the compound of formula (4) HX, where HX is hydrochloric acid

c) removing the PG hydroxyl protecting group from the products of steps a) or b), by hydrogenation in the presence of a catalyst and an organic solvent to provide olodaterol or a pharmaceutical salt thereof, preferably the R-enantiomer of olodaterol hydrochloride , Y

optionally treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride

The present invention also encompasses a process for the purification of olodaterol or a salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, said process comprising preparing the salt of camphorsulfonate of intermediate (4) according to the first aspect of the invention, preferably the salt of (R)-camphorsulfonate, according to the process of the second aspect and converting it into olodaterol or salt thereof, preferably the R-enantiomer of hydrochloride of olodaterol.

1,1-dimethyl-2-(4-methoxyphenyl) ethyl amine L-tartrate salt (not included in the invention)

The inventors of the present invention have found that the hydrochloride salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine of the prior art rapidly absorbs water up to 4% by weight, after standing under normal conditions. environmental conditions, and rapidly transforms into a hemihydrate. This behavior not only implies handling problems but also the absorbed water can react with the amine intermediate to generate more impurities. Furthermore, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride salt provided by reproducing the prior art contains at least two significant impurities, which are compounds of formula A and formula B, see Scheme 6. These impurities react as nucleophiles in a similar manner to 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine (3) in its epoxide-opening reaction with (R)-6-benzyloxy-8-oxiranyl- 4H-benzo[1,4]oxazin-3-one (2), to give impurity compounds (8) and (9), which are difficult to separate from the olodaterol intermediate (4) and the final olodaterol product, which which results in a noticeable decrease in the performance of olodaterol.

Scheme 6

Purification of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride salt, compound (3)HCl, by conventional purification techniques in various solvents was unsuccessful. See test example 1 in the experimental section. On the other hand, the present inventors have surprisingly found that 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (not included in the invention) is prepared in high purity, with low content of impurities A and B, and with high performance in a reproducible manner. Additionally, the L-tartrate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine (not included in the invention) is not hygroscopic and stable over time, which makes this intermediate easy to handle in production on an industrial scale.

Thus, the L-tartrate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, not included in the invention, is described in this description, compound of formula (3) L-tartaric acid, in where the molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to L-tartaric acid is 1:1, not included in the invention, is also described in the present description. Alternatively, the molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to L-tartaric acid is 2:1, not included in the invention, it is also described in the present description.

1,1-Dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt not included in the invention is obtained in high chemical purity and high yield, and has good stability. Advantageously, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt not included in the invention is used to prepare olodaterol or a pharmaceutically acceptable salt thereof, preferably olodaterol hydrochloride, with high purity and reproducibly high yield, having low concentrations of undesirable impurities of formula (8) and (9).

Solid forms of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt not included in the invention are described in the present description.

Preferably, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is in solid crystalline form. More preferably, the solid crystalline form of the L-tartrate salt, not included in the invention, is in anhydrous form.

Furthermore, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is in a non-crystalline (amorphous) solid form.

Also, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is in the form of a solvate (including hydrates).

Furthermore, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is characterized by a DSC thermogram showing an endothermic peak with an onset at 209-211° c.

Furthermore, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is characterized in that it provides a DSC thermogram substantially in accordance with Figure 1.

Furthermore, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is characterized in that it provides a TG thermogram substantially in accordance with Figure 2.

The 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, is characterized by an IR spectrum showing the following bands at 3386, 3283, 3207, 2995, 2956 , 2908, 1648, 1507, 1252, 1121 and 823 cmr1. Furthermore, the L-tartrate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, not included in the invention, is characterized in that it provides an IR spectrum substantially in accordance with Figure 3.

Furthermore, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, not included in the invention, may be in pure form or when mixed with other materials, for example, other polymorphs, solvates or reaction solvent residues or side products or by-products.

A process for preparing 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt as defined above, which is not encompassed by the invention, is described herein, comprising the steps of:

a) treating 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, compound of formula (3), with L-tartaric acid in the presence of a solvent, preferably in the presence of a mixture of an organic solvent and water

b) isolating the L-tartrate salt obtained in step a).

The molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to L-tartaric acid used in the aforementioned process is at least 1:1. Alternatively, the molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to L-tartaric acid used in the aforementioned process is 2:1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent comprises an organic solvent, water, or mixtures thereof. The suitable organic solvent is a polar solvent. Preferably, the solvent comprises a mixture of a polar solvent and water. Suitable polar solvents are alcohols, ester solvents and ketones. More preferably, the solvent comprises a mixture of an alcohol and water. Suitable alcohols are straight or branched C1-C6 alcohols, such as methanol, ethanol, 1-propanol, isopropanol, and mixtures thereof. Preferably, the solvent comprises a mixture of an alcohol and water in a ratio of 10:1 to 1:10 (v/v). More preferably, the solvent comprises a mixture of an alcohol and water in a ratio of 10:1 to 1:1 (v/v). Also more preferably, the solvent comprises a mixture of an alcohol and water in a ratio of 7:1 to 3:1 (v/v) as the yield increases.

Step b), the isolation of the salt obtained in step a), can be carried out by conventional means, such as filtration followed optionally by washing.

The L-tartrate salt can be purified by conventional purification techniques. Preferably, the L-tartrate salt can be purified by crystallization.

In the process described above, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine of formula (3) can be prepared comprising the steps of:

[ 3 ]

a) treating the compound of formula (6) with a methylating agent in the presence of a base and an organic solvent

to provide the compound of formula (7)

^MeO

XX (T x ) », ;

Y

b) converting the compound of formula (7) obtained in step a) into the amine of formula (3) by hydrogenation in the presence of a catalyst and an organic solvent.

Advantageously, the L-tartrate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine not included in the invention that can be obtained by the process described above, contains less than 0.1% (w/w) of impurity of formula (A) and/or less than 0.1% (w/w) of impurity of formula (B), relative to the amount of L-tartrate salt of 1,1-dimethyl-2-( 4-methoxyphenyl)ethyl amine measured by HPLC. Preferably, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt not included in the invention contains less than 0.05% (w/w) of impurity of formula (A) and/or less than 0.05% (w/w) of formula (B) impurity, relative to the amount of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt measured by HPLC.

1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate salt (not included in the invention)

As explained with respect to 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt, using the hydrochloride salt in the synthesis of olodaterol entails several difficulties due to its hygroscopicity, including poor effect. purification of impurities, such as compounds of formula (A) and (B) represented in Scheme 6 and also other impurity (C) whose chemical nature has not been established. The inventors have surprisingly discovered that using the maleate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, not included in the invention, enables the aforementioned impurity to be reduced or even eliminated. Thus, using this salt is advantageous in the production of olodaterol or pharmaceutically acceptable salts thereof with very low content of impurities. Thus, the maleate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, the compound of formula (3)-maleic acid and solid forms thereof, not covered by the invention, are described herein description.

1,1-Dimethyl-2-(4-methoxyphenyl)ethyl amine maleate salt, not included in the invention, is obtained in high chemical purity and high yield, and has good stability.

The molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to maleic acid can be 2:1. Alternatively, the molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to maleic acid can be 1:1.

The maleate salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine, not included in the invention, may be in solid form. Preferably, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate salt, not included in the invention, is in solid crystalline form. Alternatively, 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate salt, not included in the invention, is in a non-crystalline (ie amorphous) solid form.

The present description describes a process to prepare the maleate salt as defined above, which is not included in the invention, the process comprises the steps of:

a) treating the amine of formula (3) with maleic acid in the presence of a solvent

EITHER)

Y

b) isolating the maleate salt obtained in step a).

The molar ratio of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine to maleic acid used in step a) of the aforementioned process is preferably at least 1:1, more preferably 1:1 to 2 :1, even more preferably from 1:1 to 1.5:1, even more preferably from 1:1 to 1.1:1.

Suitable solvents in step a) are organic solvents as defined above. Preferably, the solvent comprises an organic solvent, water, or mixtures thereof. The suitable organic solvent is a polar solvent. Preferably, the solvent comprises an organic solvent, water, or mixtures thereof. Suitable polar solvents are alcohols, esters, ethers and solvents. Preferably, the polar solvents are esters and ethers. Suitable esters can be ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethyl malonate, and mixtures thereof. Suitable ethers can be diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane, and mixtures thereof. More preferably, the solvent used in step a) is an ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and mixtures thereof as the yield increases.

Step b), the isolation of the salt obtained in step a), can be carried out by conventional means, such as filtration followed optionally by washing.

The maleate salt can be purified by conventional purification techniques. Preferably, the maleate salt can be purified by crystallization.

In the process described above, the 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine of formula (3) can be prepared comprising the steps of:

a) treating the compound of formula (6) with a methylating agent in the presence of a base and an organic solvent

⁽ 8 ⁾

to provide the compound of formula (7)

Y

b) converting the compound of formula (7) obtained in step a) into the amine of formula (3) by hydrogenation in the presence of a catalyst and an organic solvent.

Process for the manufacture of a pharmaceutically acceptable salt of olodaterol comprising the L-tartrate salt of 1.1-dimethyl-2-(4-methoxyphenyl)ethyl amine (not included in the invention), the maleate salt of 1.1-dimethyl-2- (4-methoxyphenyl)ethyl amine (not included in the invention) and/or the camphorsulfonate salt of intermediate (4) according to the invention

A process for preparing olodaterol or a pharmaceutically acceptable salt thereof. preferably the R-enantiomer of olodaterol hydrochloride. comprising at least the stages of:

a1) treating the L-tartrate salt. compound of formula (3) L-tartaric acid. or as defined above. which can be obtained through a process as defined above.

(3)-L-tartaric acid

with a base in the presence of a mixture of an organic solvent and water to provide the amine of formula (3)

either

a2) treating the maleate salt. compound of formula (3) - maleic acid. as defined above. which can be obtained by the process as defined above.

(3)-maleic acid

with a base in the presence of a mixture of an organic solvent and water to provide the amine of formula (3)

(3)

b) reacting the amine of formula (3) obtained in step a1) or a2) with epoxide of formula (2), where PG is C ¹ -C ¹⁰ alkyl substituted by a C ⁶ -C ¹⁰ aryl group. in the presence of an organic solvent

to provide the compound of formula (4)

c) treating the compound of formula (4) obtained in step b) with a pharmaceutically acceptable HX acid. wherein the acid HX is camphorsulfonic acid to provide the compound of formula (4) HX. in it that PG is a hydroxyl protecting group as defined above

d) removing the PG hydroxyl protecting group from the products obtained in step b) or c), when it is present by hydrogenation in the presence of a catalyst and an organic solvent to provide olodaterol or a pharmaceutical salt thereof, preferably olodaterol hydrochloride, Y

e) optionally, treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt thereof.

A process not encompassed by the invention may proceed through step a1), preferably through step a1) and wherein hX in step c) is hydrochloric acid. Alternatively, a process not encompassed by the invention may proceed through step a2), preferably through step a2) and wherein HX in step c) is hydrochloric acid.

The bases suitable for step a1) and for step a2) can be inorganic bases selected from hydroxides, carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and cesium and mixtures thereof. The amount of base used may be at least a 1:1 molar ratio of base to L-tartrate salt, preferably a molar ratio of 1:1 to 10:1, more preferably 1:1 to 5 :1, even more preferably from 1:1 to 2.5:1. The amount of base used may be at least in a 1:1 molar ratio of base to maleate salt, in particular in a molar ratio of at least 2:1, preferably in a molar ratio of 1:1 to 10: 1, more preferably from 1:1 to 5:1, even more preferably from 1:1 to 2.5:1.

PG is a hydroxyl protecting group commonly known in the art to protect phenol groups. As an example, their introduction and removal are discussed in TW Greene and GM Wuts, Protecting groups in Organic Synthesis, Third Edition, Wiley, New York, 1999. Suitable hydroxyl protecting groups are those that are stable under alkaline conditions. More preferably, the hydroxyl protecting group can be deprotected by hydrogenation, such as aralkyl groups and heteroaralkyl groups and the like. In the present invention PG is C ¹ -C ¹⁰ alkyl substituted by a C ⁶ -C ¹⁰ aryl group.

"Alkyl" means a straight or branched chain hydrocarbon chain radical containing no unsaturation and having from 1 to 10 carbon atoms, represented as C ¹ -C ¹⁰ alkyl. Said alkyl groups can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, linear or branched pentyl, linear or branched hexyl, linear or branched heptyl, linear or branched nonyl or linear or branched decile. Preferably, the alkyl group is C ¹ -C ⁴ alkyl.

Aryl means an aromatic hydrocarbon radical having 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl radical may be optionally substituted with one or more substituents such as OH, SH, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, acyl as defined herein.

Aralkyl means C ¹ -C ¹⁰ alkyl as defined above substituted with C ⁶ -C ¹⁰ aryl as defined above. Preferably, the aralkyl group is a C ¹ -C ⁴ alkyl group, substituted by a C ⁶ -C ¹⁰ aryl group such as phenyl, tolyl, xylyl and naphthyl. ^C 6 ^'C 10 aryl groups may also be substituted with one or more substituents on the ring. Suitable substituents are selected from alkyl, alkoxy, halogen, as defined herein, and nitro. Preferred substituents are alkyl and alkoxy groups. Preferred aralkyl groups are 4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl or p-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl or o-nitrobenzyl, 2,4-dinitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl. More preferably, the aralkyl is benzyl or p-methoxybenzyl. Even more preferably, the aralkyl is benzyl.

"Heteroaralkyl" means straight or branched chain aralkyl as defined above, which may include one of the aforementioned C ⁶ -C ¹⁰ aryl-C ¹ -C ¹⁰ alkyl groups substituted with one or more heterocyclic groups. Preferably, the aralkyl group is C ⁶ -C ¹⁰ aryl-C ¹ -C ⁴ alkyl substituted with one or more heterocyclic groups.

In one embodiment, the PG hydroxyl protecting groups are those that can be deprotected by hydrogenation such as 4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl, 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,6 -dimethoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 2,4-dinitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl. Preferably, the hydroxyl protecting group PG is benzyl and 4-methoxybenzyl. More preferably, the hydroxyl protecting group PG is benzyl.

The compound of intermediate formula (2) is known in the art. Preferably, the compound of formula (2) in which the hydroxyl protecting group is benzyl, (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one, is prepared according to with prior art document no. WO 2008/090193 A2.

The organic solvent of step b) is as defined above. Preferably, the organic solvent is selected from the group consisting of an ether solvent (for example, diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl phenyl ether or anisole), an aromatic hydrocarbon solvent (for example, benzene, toluene, o-xylene, m-xylene, and p-xylene), alcohol solvents (for example, methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m -cresol), ketone solvents (for example, acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone), ester solvents (for example, ethyl formate, methyl acetate, ethyl acetate , isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate) and N,N-dimethylformamide, N,N,-dimethylac etamide, dimethylsulfoxide, and acetonitrile, propionitrile, and butyronitrile. More preferably, the organic solvent of step b) is selected from 2-methyltetrahydrofuran, 1,4-dioxane, anisole, toluene, ethylene glycol and acetonitrile.

In another embodiment, step b) can be carried out without the presence of an organic solvent.

The pharmaceutically acceptable HX acid of step c) encompassed by the process of the invention is camphorsulfonic acid.

In a preferred embodiment, the pharmaceutically acceptable salt of olodaterol is the hydrochloride salt, prepared by the process of the invention, which can be further purified. More preferably, the pharmaceutically acceptable salt of olodaterol, preferably olodaterol hydrochloride, can be purified by recrystallization.

In the process of the invention, step c) is carried out and the acid HX is camphorsulfonic acid, which provides the camphorsulfonate salt of intermediate (4) as defined in the first aspect. Preferably, step c) further comprises converting the camphorsulfonate salt of intermediate (4) (ie HX is camphorsulfonic acid) to the hydrochloride salt of intermediate (4) (ie HX is hydrochloric acid). This involves treating the camphorsulfonate salt of compound (4), where PG is a hydroxyl protecting group as defined above, with hydrochloric acid (which may be present as a gas or an aqueous solution or generated in situ, e.g. from an alkylsilyl halide in the presence of a protic solvent (such as an alcohol; i.e., methanol, ethanol, isopropanol, 1-propanol, and 1-butanol) in the presence of a suitable organic solvent or solvent mixtures. may be selected from alcohols, ethers, esters, chlorinated hydrocarbons and mixtures thereof or aqueous mixtures thereof Preferably, the organic solvent is selected from the group consisting of alcohols, ethers and esters In a more preferred embodiment, the salt of camphorsulfonate of intermediate (4) is converted to the free base (i.e. compound of formula (4)), for example by treatment with a suitable base (which may be inorganic bases). cas selected from hydroxides, carbonates and bicarbonates of calcium, sodium, magnesium, potassium, lithium and cesium and mixtures thereof), preferably in the presence of a suitable organic solvent as previously defined, preferably a polar solvent such as an ester and ether or mixtures thereof. The compound of formula (4) free base is then reacted with hydrochloric acid (which may be present as a gas or as an aqueous solution or generated in situ, for example, from an alkylsilyl halide in the presence of a protic solvent (as an alcohol; i.e., methanol, ethanol, isopropanol, 1-propanol, and 1-butanol) in the presence of an organic solvent as defined above, to provide the corresponding salt of intermediate (4).Most preferably, the salt of intermediate (4) is isolated, for example by filtration optionally followed by washing (such as washing with an ester, preferably ethyl acetate).

The hydrogenation step d) is carried out in the presence of a catalyst and an organic solvent. Suitable catalysts are selected from Pd, Pt, Rh, Ru, Ni, Fe, Zn and Ir catalysts. Preferably, the suitable catalyst is selected from palladium (0) (Pd(0)), palladium hydroxide (Pd(OH ) ² ), palladium on activated carbon (Pd/C), palladium on alumina, powdered palladium on carbon, platinum, platinum on activated carbon, and Raney™ Nickel. A combination of catalysts can also be used. Most preferably, the catalyst is palladium on activated carbon and palladium hydroxide (Pd(OH) ² ). The amount of catalyst is not critical and can be equal to or less than 10% by weight of the amount of compound of formula (4). Furthermore, the hydrogenation takes place in a hydrogen pressure range of 0.5 to 10 atm. Most preferably, the hydrogen pressure is 0.5 to 5 atm since fewer impurities are generated.

In a particular embodiment of the third aspect of the present invention, the process for preparing the R-enantiomer of olodaterol hydrochloride comprises at least the steps of:

a1) treating the L-tartrate salt, compound of formula (3) L-tartaric acid, as defined above, which can be obtained through the process defined above,

(3)-L-tartaric acid

with a base in the presence of a mixture of an organic solvent and water to provide the amine of formula (3)

a2) treat the maleate salt, compound of formula (3) -maleic acid, or as defined above, which can be obtained through the process defined above,

(3)-maleic acid

with a base in the presence of a mixture of an organic solvent and water to provide the amine of formula (3)

b) reacting the amine of formula (3) obtained in step a1) or a2) with epoxide of formula (2), where PG is C ¹ -C ¹⁰ alkyl substituted by a C ⁶ -C ¹⁰ aryl group, in presence of an organic solvent,

to provide the compound of formula (4)

c) treating the compound of formula (4) obtained in step b) with a pharmaceutically acceptable HX acid which is camphorsulfonic acid, to provide the compound of formula (4) HX, wherein PG is a hydroxyl protecting group as shown previously defined

d) removing the PG hydroxyl protecting group from the product obtained in step c) by hydrogenation in the presence of a catalyst and an organic solvent to provide olodaterol or a pharmaceutical salt thereof, the compound of formula (1) HX

e) converting the pharmaceutical salt of olodaterol obtained in step d), where HX is not hydrochloric acid, into the hydrochloride salt of olodaterol.

In one embodiment, the process goes through step a1). In an alternative embodiment, the process goes through step a2).

A further embodiment of the third aspect of the present invention provides a process for preparing olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, comprising at least the steps of:

a) reacting an amine of formula (3) with epoxide of formula (2), where PG is C1- ^C10 alkyl substituted by ^a C6- ^{C10 aryl} group, in the presence of an organic solvent

to provide the compound of formula (4)

b) treating the compound of formula (4) obtained in step a) with camphorsulfonic acid, preferably (R)-camphorsulfonic acid, to provide the camphorsulfonate salt of intermediate (4), where PG is a protecting group of hydroxyl as defined above,

c) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid, to provide the compound of formula (4) HX, where HX is hydrochloric acid,

d) removing the PG hydroxyl protecting group from the products obtained in step b) or c), by hydrogenation in the presence of a catalyst and an organic solvent to provide olodaterol or a pharmaceutical salt thereof, preferably the R-enantiomer of olodaterol hydrochloride , Y

e) optionally, treating the olodaterol obtained in step d) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

Particularly, camphorsulfonic acid, preferably (R)-camphorsulfonic acid, is advantageous for the purification of advanced intermediate (4) from impurities IMP-1, IMP-2, IMP-3 and IMP-4, and thus, for provide final olodaterol or the salt thereof, preferably the R-enantiomer of olodaterol hydrochloride, of high chemical and enantiomeric purity.

The amine compound (3) can be obtained according to any of the processes described above. In the process described above, preferably PG is benzyl.

Step b) is preferably carried out as described in the second aspect of the present invention. Step c) is optional. Thus, in one embodiment step c) is carried out. In an alternative embodiment, step c) is not carried out. This step involves treating the camphorsulfonate salt of compound (4), where PG is a hydroxyl protecting group as defined above, with hydrochloric acid (ie HX is hydrochloric acid). In a particular embodiment, the camphorsulfonate salt of intermediate (4) is converted to the free base (i.e. compound (4)), for example by treatment with a suitable base such as aqueous sodium hydroxide, preferably in the presence of a suitable organic solvent as previously defined, such as an ester, preferably ethyl acetate. The free base of compound (4) is then converted to the hydrochloride salt by treatment with hydrochloric acid (i.e. HX is hydrochloric acid), preferably in the presence of a suitable organic solvent as previously defined, such as an ester, preferably ethyl acetate. More preferably, the hydrochloride salt is isolated, for example, by filtration optionally followed by washing (such as washing with an ester, preferably ethyl acetate).

Steps d) and e) can be carried out as previously described in the present description.

In an even more preferred embodiment of the third aspect of the present invention, a process is provided to prepare the R-enantiomer of olodaterol hydrochloride, comprising at least the steps of:

a) reacting an amine of formula (3) with epoxide of formula (2), where PG is C1- ^C10 alkyl substituted by ^a C6- ^{C10 aryl} group, in the presence of an organic solvent

to provide the compound of formula (4)

b) treating the compound of formula (4) obtained in step a) with (R)-camphorsulfonic acid, to provide the (R)-camphorsulfonate salt of intermediate (4), where PG is a hydroxyl protecting group as defined above,

(4)-(R)-camphorsulfonic acid

c) treating the (R)-camphorsulfonate salt of compound (4) with hydrochloric acid, to provide the compound of formula (4) HX, wherein PG is a hydroxyl protecting group as defined above and HX is hydrochloric acid ,

d) removing the PG hydroxyl protecting group from the product obtained in step c), by hydrogenation in the presence of a catalyst and an organic solvent to provide the R-enantiomer of olodaterol hydrochloride

The amine compound (3) can be obtained according to any of the processes described above. In the process described above, preferably PG is benzyl.

Steps a), b), c) and d) can be carried out as previously described in the present description.

The use of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt as defined above to prepare olodaterol or a pharmaceutically acceptable salt thereof is described in the present description, preferably the R-enantiomer olodaterol hydrochloride.

The use of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate salt as defined above to prepare olodaterol or a pharmaceutically acceptable salt thereof is described herein, preferably the R-enantiomer of hydrochloride of olodaterol.

A further aspect of the present invention relates to the use of the camphorsulfonate salt of intermediate (4) as defined in the first and second aspects to prepare olodaterol or a pharmaceutically acceptable salt thereof, preferably the R-enantiomer of olodaterol hydrochloride.

In the following, the present invention is further illustrated by way of examples. In no case should they be construed as limiting the scope of the invention as defined in the claims.

experiments

General methods

Proton Nuclear Magnetic Resonance (1H NMR) analyzes were recorded in a deuterated solvent (d6-DMSO) on a Varian Gemini 200 Fourier transform (FT) NMR spectrometer and chemical shifts are given in parts per million (ppm). ) downfield from the residual solvent peak as internal standard. Coupling constants are given in Hz. Spectra were acquired by dissolving 5-10 mg of sample in 0.7 mL of deuterated solvent.

Differential Scanning Calorimetry (DSC) analyzes were recorded on a Mettler Toledo DSC822e calorimeter. Experimental conditions: Aluminum crucibles 40 pL; dry nitrogen atmosphere at a flow rate of 50 mL/min; heating rate of 10 °C/min between 30 and 300 °C. Data collection and data evaluation was performed with the STARe software.

Thermogravimetric (TG) analyzes were recorded on a Mettler Toledo SDTA851e thermobalance. Experimental conditions: Aluminum crucibles 40 pL; dry nitrogen atmosphere at a flow rate of 80 ml/min; heating rate of 10 °C/min between 30 and 300 °C. Data collection and data evaluation was performed with the STARe software.

Infrared (IR) spectrometry analyzes were recorded on a Perkin Elmer One FT-IR Spectrometer using a Perkin Elmer ATR accessory.

Karl Fischer (KF) analyzes were performed on a Metrohm 701 KF Titrino, equipped with a Metrohm 6.0338.100 electrode and 684/737 coulometer (diaphragm cell), using A ^q UAMETRIC Composite 5 as reagent.

examples

Example 1. 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride

To a suspension of 4-(2-methyl-2-nitropropyl)phenol (50.0 g, 256.1 mmol), K ² CO ³ (38.9 g, 281.7 mmol, 1.1 equiv) in acetone (200 mL) at room temperature, dimethyl sulfate (26.7 mL, 35.5 g, 281.7 mmol, 1.1 equiv) is carefully added dropwise under inert atmosphere. The resulting mixture was stirred at 58°C for 4 hours under an inert atmosphere and cooled to room temperature. Aqueous 1M NaOH solution (120 mL) was added and the resulting mixture was stirred for 90 min at room temperature. Then toluene (150 mL) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The organic phase solvent was removed by distillation under reduced pressure at a maximum temperature of 45 °C. Subsequently, ethanol (150 mL) was added and removed by distillation at a maximum temperature of 45 °C. The obtained brown oil was mixed with ethanol (400 mL) and hydrogenated under 15 atm hydrogen pressure with Raney Ni (10.0 g) at 50 °C for 5 hours. The resulting mixture was filtered through a pad of celite and washed with ethanol. The filtrate was removed by distillation under reduced pressure at a maximum temperature of 45°C. Then, ethyl acetate (250 mL) was added and partially distilled off at atmospheric pressure. The resulting mixture was then cooled to 70°C and a 4M solution of hydrochloric acid in ethyl acetate (71.5 mL) was added over 5 min. The resulting mixture was cooled to room temperature over 2 hours and stirred for an additional 2 hours. The white solid obtained was filtered and washed with ethyl acetate.

Yield: 41.3g (72%)

KF: 3.7-4%

DSC (10 °C/min): First broad endothermic peak starting at 86 °C, due to water evaporation, second sharp endothermic peak starting at 170 °C, due to melting.

TG (10 °C/min): Weight loss of 3.9% by weight from 30 °C to 100 °C due to evaporation of water and additional weight loss from 180 °C due to decomposition.

Purity (HPLC): 98.0%. Significant impurities: 0.05% (compound A), 1.03% (compound B), 0.84% (compound C not characterized).

Test Example 1 Purification effect of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride

The hydrochloride salt obtained from example 1 was treated with various solvents in order to reject the presence of significant impurities (compounds A and B). The results obtained are collected in the table below, which demonstrates the poor purification effect of the hydrochloride salt of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine.

General slurry procedure: 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride (5.0 g) was suspended in 50 mL of solvent, heated to the reflux temperature of the solvent and stirred for 45 min. Then the resulting suspension was cooled to room temperature and stirred for 2 hours. The solid obtained was removed by filtration, washed with solvent and dried at 45 °C under atmospheric pressure.

General crystallization procedure: 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hydrochloride (5.0 g) was dissolved in the minimum amount of solvent and heated at the reflux temperature of the solvent until obtained. a solution. The resulting solution was then cooled to room temperature and stirred for 2 hours. The resulting solid was filtered off, washed with solvent and dried at 45°C under atmospheric pressure.

Example 2. 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate

To a suspension of 4-(2-methyl-2-nitropropyl)phenol (10.0 g, 51.2 mmol), K ² CO ³ (7.8 g, 56.3 mmol, 1.1 equiv.) in Dimethyl sulfate (5.3 mL, 7.1 g, 56.3 mmol, 1.1 eq) is carefully added dropwise to acetone (40 mL) at room temperature under inert atmosphere. The resulting mixture was stirred at 58°C for 4 hours under an inert atmosphere and cooled to room temperature. Aqueous 1M NaOH solution (24 mL) was added and the resulting mixture was stirred for 90 min at room temperature. Then toluene (30 mL) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The organic phase solvent was removed by distillation under reduced pressure at a maximum temperature of 45 °C. Subsequently, ethanol (30 mL) was added and removed by distillation at a maximum temperature of 45 °C. The brown oil obtained was mixed with ethanol (80 mL) and hydrogenated at 15 atm of hydrogen pressure with Raney Ni (2.0 g), at 50 °C and for 5 hours. The resulting suspension was filtered through a pad of celite, washed with ethanol and distilled off under reduced pressure at a maximum temperature of 45°C. Then, the brownish oil obtained was dissolved in ethanol (50 mL) at 50 °C, and a solution of L-tartaric acid (7.7 g, 1.0 equiv.) in water (10 mL) was added dropwise. The resulting white suspension was stirred at 40-45°C for 1 hour, cooled to room temperature over 1 hour, and further stirred for 1 hour. The obtained crystals were filtered off and washed with a mixture of ethanol and water (5:1; v/v).

Yield: 14.0g (83%)

KF: 0.5%

Purity (HPLC): 98.8%. Significant impurities: 0.14% (compound A), 0.11% (compound B), 0.04% (compound C not characterized).

Example 3. Recrystallization of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate

The 1,1-dimethyl-2-(4-methoxyphenyl)ethyl-amine L-tartrate obtained in example 2 (1 g) was suspended in ethanol (5 mL) and heated to reflux temperature. Then, water (2 mL) was added dropwise with the reflux temperature maintained. The resulting solution was seeded, cooled to room temperature over 1 hour and further stirred for 1 hour, and finally cooled to 0-5°C over 1 hour. The resulting suspension was filtered and washed with a cold mixture of ethanol and water (5:2; v v) to give 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate as an off-white solid. .

Yield: 0.9g (90%)

Purity (HPLC): 99.5%. Significant impurities: 0.02% (compound A), 0.03% (compound B).

DSC (10 °C/min): Acute endothermic peak with onset at 209-211 °C.

TG (10 °C/min): Weight loss from 180-190 °C due to decomposition.

¹ H-NMR (200 MHz, 6-DMSO): 6/ppm 8.00-7.00 (s, 6H, NH, OH), 7.14 (d, J 10 Hz, 2H, aromatic H), 6 0.90 (d, J 10 Hz, 2H, aromatic H), 3.96 (s, 2H, CHOH), 3.73 (s, 3H, OCH ³ ), 2.78 (s, 2H, CH ² ), 1.17 (s, 6H, 2 CH ³ ).

Example 4. Preparation of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1, hydrochloride 4,]oxazin-3-one

The 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (1.66 g, 5 mmol) obtained from example 3 was partitioned between toluene (10 mL) and 1 M aqueous NaOH solution. (11 mL, 2.2 equiv). The aqueous phase was extracted with toluene and the organic phases obtained were combined and washed with water. The organic phase solvent was distilled off under reduced pressure to give 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine as a brownish oil. Then (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one (1.0 g, 3.4 mmol) and 1,4-dioxane (10 mL) were added. and the resulting mixture was heated at 97°C for 17 hours. Subsequently, the mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Then, 1,4-dioxane (2 mL) and ethanol (10 mL) were added to the resulting residue, and a 37% w/v aqueous hydrochloric acid solution (410 pL, 1.4 equiv.) was added dropwise. . The resulting mixture was stirred at room temperature for 2 hours, filtered, washed with ethanol and dried at 40-50°C under atmospheric pressure.

Yield: 85-90%

Purity (HPLC): 95.0-99.9%

Enantiomeric purity (chiral HPLC): 97.0-99.9%

Example 5. Preparation of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3( 4H)-one

A mixture of (R)-6-(benzyloxy)-8[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-4H-benzo[1,4,]oxazin- 3-one (600 mg, 1.2 mmol) obtained from example 4, 5% palladium on charcoal (40 mg) and methanol (40 mL) was hydrogenated under 3 atm hydrogen pressure at 40°C for 5 hours. The resulting suspension was filtered through a pad of Celite. The filtrate was distilled under reduced pressure, and the resulting residue was recrystallized from a mixture of methanol and isopropanol. The suspension was filtered, washed with cold ethanol and dried.

Yield: 85-90%

Purity (HPLC): 95.0-99.9%

Enantiomeric purity (chiral HPLC method): 97.0-99.9%

Example 6. Purification of ®-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1,4,]oxazin -3-one

(R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-benzo[1,4,] hydrochloride was stirred oxazin-3-one (5.6 g, 10.9 mmol; 95.0% purity; 98.3% enantiomeric purity) as obtained in example 4 with ethyl acetate (50 mL) and an aqueous solution 1M sodium hydroxide (50 mL). The aqueous phase was extracted with ethyl acetate and the organic phases obtained were combined and washed with water. The organic phase solvent was distilled off under reduced pressure to give a brownish oil. Ethyl acetate (25 mL) was added to the obtained oil and a suspension of (R)-(-)-10-camphorsulfonic acid (2.8 g, 12 mmol, 1.0 equiv.) in ethyl acetate ( 5.6 mL) and THF (2.8 mL). The resulting suspension was stirred at room temperature for 12 hours, filtered and washed with a mixture of ethyl acetate and THF (5:1) to give the corresponding salt of (R)-(-)-10-camphorsulfonate as a solution. off-white solid.

Yield: 6.4g

Purity (HPLC): 99.3%. Important impurities: 0.10% (IMP-1), 0.20% (IMP-2) and 0.50%

(IMP-4). Enantiomeric purity (chiral HPLC): 100% (ND IMP-3)

The solid was recrystallized from a mixture of ethyl acetate and THF (13:4). Yield: 93%. Purity (HPLC): 99.8%. Enantiomeric purity (chiral HPLC): 100%.

¹ H-NMR (200 MHz, d6-DMSO): 6/ppm 9.21 (s, 1H), 9.03 (s, 1H), 7.93 (s, 1H), 7.31-7.26 (m, 5H, OCH ² Ph), 7.12 (d, J 10 Hz, 1H, aromatic H), 6.94 (d, J 4 Hz, 1H, aromatic H), 6.82 (d, J 10 Hz, 1H, aromatic H), 6.54 (d, J 4 Hz, 1H, aromatic H), 6.14 (s, 1H), 5.44 (s, 1H, CHOH), 4.90 (s, 2H, OCH ² Ph). 4.42 (d, J 28 Hz, 1H, COCH ^a H ^b ), 4.35 (d, J 28 Hz, 1H, COCH ^a H ^b ), 3.76 (s, 3H, OCH ^a ), 3, 45 (d, J 16 Hz, 1H, CHOHCH ^to H ^b NH), 2.92 (d, J 16 Hz, 1H, CHOHCH ^to H ^b NH), 3.36-1.70 (m, 11H, 1, 33 (s, 3H), 1.10 (s, 3H, CH ³ ), 0.83 (s, 3H, CH ³ ).

¹³ C-NMR (50 MHz, d6-DMSO): 6/ppm 216.65, 166.03, 158.92, 154.53, 126.95-137.05, 113.95, 107.03, 103, 54, 70.53, 67.36, 64.57, 60.94, 58.66, 55.33, 42.83-48.06, 27.14, 24.86, 22.94, 22.80, 20.17, 19.98.

DSC (10 °C/min): Acute endothermic peak with onset at 163-167 °C.

TG (10 °C/min): Weight loss from 210 °C due to decomposition.

IR (cm ^-1 ): 2955.7, 1745.4, 1702.1, 1617.9, 1513.7, 1470.4, 1369.7, 1329.5, 1250.0, 1162.2, 1051.5 , 1038.3, 852.0, 746.7, 700.4.

Example 7. Preparation of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethyl-amino]ethyl]-4H-benzo[ Purified 1,4,]oxazin-3-one

The (R)-(-)-10-camphorsulfonate salt (1.4 g, 1.97 mmol) obtained in example 6 was stirred with ethyl acetate (14 mL) and 1 M aqueous sodium hydroxide solution. (5mL). The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with brine. A 4N aqueous solution of HCl in ethyl acetate was added until the pH was 1-2. The resulting suspension was stirred at room temperature for 30 min and at 0-5 °C for a further 30 min, filtered, washed with cold ethyl acetate and dried.

Yield: 1.0g

Purity (HPLC): 99.3%

Enantiomeric purity (chiral HPLC): 100%

Example 8. Preparation of (R)-6-hydroxy-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylaminoethyl]-2H-1,4-benzoxazin-3( 4H)-one purified

A suspension of the hydrochloride salt (913 mg, 1.77 mmol), as obtained in example 7, and palladium on carbon JM 452 (5%) in methanol (40 mL) was hydrogenated with H ² at 3 atm. hydrogen pressure at 40 °C for 5 hours. The resulting suspension was filtered through a pad of Celite. The filtrate was distilled under reduced pressure, and the resulting residue was recrystallized from a mixture of methanol and isopropanol. The suspension was filtered, washed with cold ethanol and dried.

Yield: 85-90%

Purity (HPLC): 99.0 - 99.9%

Enantiomeric purity (chiral HPLC method): 99.0-100%

Example 9. Preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine maleate

To a suspension of 4-(2-methyl-2-nitropropyl)phenol 100 g, 512 mmol), K ² CO ³ (77.8 g, 563 mmol, 1.1 equiv.) in acetone (300 mL) at room temperature room, dimethyl sulfate (53.3 mL, 562 mmol, 1.1 equiv.) was carefully added dropwise under inert atmosphere. The dimethyl sulfate addition line was rinsed with acetone (100 mL) and added to the reaction. The resulting mixture was stirred at reflux temperature for 4 hours and cooled to room temperature. Then 1M aqueous NaOH solution (240 mL) was added and the system was stirred for 90 min. Subsequently, toluene (300 mL) was added and the phases were separated. The aqueous phase was extracted with toluene and the organic phases were combined and washed with water. The brownish oil (97.8% purity) obtained was dissolved in ethanol (800 mL). Half of the solution was hydrogenated under 15 atm hydrogen pressure with Raney Ni (10.0 g) at 50 °C for 12 hours. The resulting mixture was filtered through a pad of celite and 1/3 of the solution was used and filtered off. The brownish oil obtained was mixed with maleic acid (9.9 g, 85.3 mmol, 1.0 equiv.) and ethyl acetate (113 mL). The resulting suspension was heated to 50°C and stirred until solution was obtained and cooled to room temperature over 12 hours. The obtained solid was filtered and washed with ethyl acetate.

Yield: 17.5g (74%)

Purity (HPLC): 99.2%. Significant impurities: 0.04% (compound A), ND (compound B), ND (compound C not characterized).

1H-NMR (200 MHz, d6-DMSO), 6/ppm 7.78 (broad s, 3H, NH,OH), 7.14 (d, J 8 Hz, 2H, aromatic H), 6.92 (d , J 8 Hz, 2H, aromatic), 6.03 (s, 2H, CH=COOH), 3.74 (s, 3H, OCH ³ ), 2.76 (s, 2H, CH ² Ph), 1, 18 (s, 6H, 2 CH ³ ).

DSC (10 °C/min): Acute endothermic peak with onset at 96-99 °C.

TG (10 °C/min): Weight loss from 130 °C due to decomposition.

Example 10. Preparation of 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine hemimaleate

The second half of the solution obtained in example 9 was hydrogenated at 15 atm hydrogen pressure with Raney Ni (10.0 g) at 50 °C for 12 hours. The resulting mixture was filtered through a pad of celite and 1/2 of the solution was distilled. The brownish oil obtained was mixed with maleic acid (7.4 g, 63.8 mmol, 0.5 equiv.) and ethyl acetate (125 mL). The resulting suspension was heated to 50°C and stirred until solution was obtained and cooled to room temperature for 2 hours. The obtained solid was filtered and washed with ethyl acetate.

Yield: 23g (76%)

Purity (HPLC): 99.3% Significant impurities: 0.09% (compound A), ND (compound B), 0.05% (compound C not characterized).

1H-NMR (200 MHz, d6-DMSO), 6/ppm 7.11 (d, J 8 Hz, 2H, aromatic H), 6.88 (d, J 8 Hz, 2H, aromatic), 6.03 ( s, 1H, CH=COOH), 4.5-4.0 (broad s, 3H, NH,OH), 3.73 (s, 3H, OCH ³ ), 2.63 (s, 2H, CH ² Ph ), 1.07 (s, 6H, 2 CH ³ ).

Example 11. Preparation of 4-(2-methyl-2-nitropropyl)phenol

A suspension of 4-hydroxybenzyl alcohol (1 kg, 8.06 mol), potassium hydroxide (0.23 kg, 4.03 mol, 0.5 equiv), and tetrabutylammonium bromide (TBAB) (0.01 kg, 1% w/v) in toluene (3.0 L) heated at 85-90 °C for 48 hours. The resulting mixture was cooled to room temperature and 1N aqueous HCl solution was added until a pH of 6-7 was observed. The solvent was removed by distillation. Then, ethyl acetate and water were added to the resulting residue, and the layers were separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined and washed with water. The organic phases were distilled off to give 4-(2-methyl-2-nitropropyl)phenol as a brown solid, which was recrystallized from a mixture of ethyl acetate and methylcyclohexane.

Yield: 1.42g (78%)

Purity (HPLC): 97.0-98.0%

Example 12. Preparation of (R)-6-(benzyloxy)-8-[1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl]-4H-camphorsulfonate benzo[1,4,]oxazin-3-one

1,1-Dimethyl-2-(4-methoxyphenyl)ethyl amine L-tartrate salt (4.9 g, 14.9 mmol) was partitioned between toluene (50 mL) and 1 M aqueous NaOH solution ( 50mL). The aqueous phase was extracted with toluene and the obtained organic phases were combined and washed with water and brine. The organic phase solvent was distilled off under reduced pressure to give 1,1-dimethyl-2-(4-methoxyphenyl)ethyl amine as a brownish oil. Then (R)-6-benzyloxy-8-oxiranyl-4H-benzo[1,4]oxazin-3-one (3.4 g, 11.4 mmol) and 1,4-dioxane (20 mL) were added. and the resulting mixture was heated at 97 °C for 16 hours in an inert atmosphere. Subsequently, the mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure to give a residue. Then ethyl acetate (47 mL) and a solution of (R)-camphorsulfonic acid (3.4 g, 15.0 mmol) in tetrahydrofuran (28 mL) were added. The resulting solution was seeded, stirred at room temperature, filtered, washed with a mixture of ethyl acetate and tetrahydrofuran (5:1), and dried.

Yield: 4.0g (48%)

Purity (HPLC): 99.5%

Enantiomeric purity (chiral HPLC): 99.9%

Claims (13)

1. A camphorsulfonate salt of intermediate ( ⁴ ), wherein the PG is C1- ^C10 alkyl substituted by a C6- ^C10 aryl group

2. The camphorsulfonate salt according to claim 1, wherein the PG is benzyl or p-methoxybenzyl. 3. The camphorsulfonate salt according to any one of claims 1 or 2, wherein the molar ratio of intermediate (4) to camphorsulfonic acid is 1:1. 4. The camphorsulfonate salt according to any one of claims 1 to 3, wherein the camphorsulfonic acid is (R)-(-)-camphorsulfonic acid. 5. The camphorsulfonate salt according to any one of claims 1 to 3, wherein the camphorsulfonic acid is (S)-(+)-camphorsulfonic acid. 6. The camphorsulfonate salt according to any one of claims 1 to 5, which is in solid crystalline form. 7. A crystalline solid form of the camphorsulfonate salt according to claim 6, characterized by at least one of the following: a) a DSC thermogram showing an endothermic peak with an onset at 163-166 °C, or b) an IR spectrum showing the following bands at 2955, 1745, 1702, 1617, 1513, 1470, 1369, 1329, 1250, 1162, 1051, 1038, 852, 746, 700 cm'1. 8. A process for preparing the camphorsulfonate salt as defined in any one of claims 1 to 7, comprising the steps of: a) treating the intermediate of formula (4) wherein PG is as defined in any one of claims 1 or 2 with camphorsulfonic acid in the presence of a solvent or a mixture of solvents

Y b) isolating the camphorsulfonate salt obtained in step a). 9. A process for the manufacture of olodaterol or a pharmaceutically acceptable salt thereof comprising the steps of: a) providing the camphorsulfonate salt of compound (4) as defined in any one of claims 1 to 7 b) optionally treating the camphorsulfonate salt of compound (4) with hydrochloric acid, to provide the compound of formula (4) HX, wherein PG is a hydroxyl protecting group as defined in step a) and HX is acid hydrochloric

c) removing the hydroxyl protecting group PG from the products of steps a) or b), by hydrogenation in the presence of a catalyst and an organic solvent to provide olodaterol or a pharmaceutically acceptable salt thereof, and d) optionally, treating the olodaterol obtained in step c) with a pharmaceutically acceptable acid to provide a pharmaceutically acceptable salt thereof. 10. The process according to claim 9, wherein step b) is carried out and comprises the additional steps of: b1) converting the camphorsulfonate salt of compound (4), as defined in any one of claims 1 to 7, into the free base in the presence of a base and a solvent and b2) treating the free base obtained in step b1), with hydrochloric acid, to provide the compound of formula (4) HX, where HX is hydrochloric acid. 11. The process according to any one of claims 9 to 10, wherein the camphorsulfonate salt in step a) is the (R)-(-)-camphorsulfonate salt. 12. The process according to any one of claims 9 to 11, wherein the camphorsulfonate salt of compound (4) is obtained by a process comprising the steps of: a) reacting an amine of formula (3) or a salt thereof with an epoxide of formula (2), wherein PG is a hydroxyl protecting group as defined in any one of claims 1 or 2, in the presence of an organic solvent

to provide the compound of formula (4)

b) treating the compound of formula (4) obtained in step a) with camphorsulfonic acid in the presence of a solvent or a mixture of solvents, wherein PG is a hydroxyl protecting group as defined in step a). 13. The process according to any one of claims 9 to 12, wherein the pharmaceutically acceptable salt of olodaterol is the R-enantiomer of olodaterol hydrochloride.